When the MERS CoV outbreak raised global health concerns, we initiated a program to develop a candidate vaccine. Starting from Spike glycoprotein (S) sequences, we developed an immunization strategy consisting of a full-length S DNA prime and a S1 subunit protein boost that elicited high titers of neutralizing antibodies against eight different MERS-CoV strains. Immune sera contained potent neutralizing antibodies targeting the receptor binding domain (RBD), non-RBD portions of S1, and the S2 subunit. From the immunized mice we produced a panel of hybridomas and produced monoclonal antibodies from which a variety with high neutralizing activity were selected for further characterization. The atomic structure of a monoclonal antibodyD12in complex with the RBD revealed two distinct mechanisms by which they block binding to the MERS-CoV receptor, DPP4. In addition, immunogenicity was measured in nonhuman primates. Thus, vaccine immunogens designed from S sequences induced a diverse repertoire of neutralizing antibodies, demonstrating an efficient approach to vaccine design that may be applicable to other emerging viruses. Studies were also initiated with the spike glycoprotein of the HKU1 beta-coronavirus.